Thienopyrimidine derivaties as aldose-reductase inhibitors

ABSTRACT

The present invention provides thienopyrimidine derivatives of the formula (I) ##STR1## wherein R 1  and R 2  are the same or different and each represent hydrogen, halogen, lower alkyl, cycloalkyl or phenyl, R 1  and R 2  taken together may form a ring of an alkylene chain, R 3  represents lower alkyl or a group of the formula ##STR2## (in which R 4  is a lower alkyl, lower alkoxy or halogen, m is 0, 1 or 2, and R 5  is hydrogen or halogen) and Z is oxygen or sulfur, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them as an active principle and aldose-reductase inhibitors.

DESCRIPTION

1. Technical Field

The present invention relates to novel thienopyrimidine derivatives orpharmaceutically acceptable salts thereof, pharmaceutical compositionscontaining the same and aldose-reductase inhibitors.

2. Background Art

Kinoshita et al. reported that the aldose-reductase participates incrisis and development of complications of diabetes such as diabeticcataract, diabetic neuropathy, diabetic nephropathy and diabeticretinopathy (J. H. Kinoshita et al., Journal of the American MedicalAssociation, 246, 257, (1981)). The aldose-reductase reduces aldosessuch as glucose and galactose to polyols such as sorbitols. The polyolproduced is relatively stable and rarely passes extracellularly,consequently accumulating intracellularly. Since the hyperglycemicstatus as in diabetes, promotes the activity of aldose-reductase, thepolyols accumulate excessively in the lenses, neurons, vascular tissues,etc. Therefore, the osmotic pressure increases in these tissue cells,which results in swell of the tissues, damaged cellular function andtissue disorders. In view of these situations, it has been desired todevelop compounds useful for remedy and prevention of various diabeticcomplications and excellent in aldose-reductose inhibiting activity byinhibiting the aldose-reductase and thus avoiding abnormal intracellularaccumulation of polyols.

DISCLOSURE OF THE INVENTION

The inventors conducted extensive research in view of the above problemsof the prior art and found that the novel thienopyrimidine derivativesrepresented below by the formula (I) and their salts exhibit outstandingaldose-reductase inhibitory effect and are useful as medicaments.Therefore, the invention has been accomplished.

The present invention provides thienopyrimidine derivatives of theformula (I) ##STR3## wherein R₁ and R₂ are the same or different andeach represent hydrogen, halogen, lower alkyl, cycloalkyl or pheny, R₁and R₂ taken together may form a ring with an alkylene chain, R₃represents lower alkyl or a group of the formula ##STR4## (in which R₄is lower alkyl, lower alkoxy or halogen, m is 0, 1 or 2, and R₅ ishydrogen or halogen) and Z is oxygen or sulfur, or pharmaceuticallyacceptable salts thereof.

Examples of halogen atoms represented by R₁, R₂, R₄ and R₅ in theformula (I) are fluorine, chlorine, bromine and iodine. Examples oflower alkyl groups represented by R₁, R₂, R₃ and R₄ are straight chainor branched chain C₁ -C₆ alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, tert-pentyl, hexyl and isohexyl. Examples of cycloalkylgroups represented by R₁ and R₂ are C₃ -C₇ cyclopropyl, cyclobutyl,cyclohexyl, etc. Examples of rings with an alkylene chain formed by R₁and R₂ taken together are ##STR5## etc. Examples of lower alkoxy groupsrepresented by R₄ are straight chain or branched chain C₁ -C₆ alkoxygroups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,tert-butoxy, pentoxy and hexyloxy.

The salts of the compounds of the present invention are pharmaceuticallyacceptable salts thereof including salts of alkali metals such assodium, potassium and lithium; salts of alkaline earth metals such ascalcium and magnesium; salts of ammonium; salts of tetraalkylammoniumssuch as tetramethylammonium, tetraethylammonium, tetrapropylammonium andtetrabutylammonium; salts of mono-, di- or trialkylamines such asmethylamine, ethylamine, isopropylamine, tert-butylamine,dimethtylamine, diethylamine, trimethylamine and triethylamine; salts ofcycloalkylamines such as cyclopentylamine and cyclohexylamine; salts ofphenyl(lower alkyl)amines such as benzylamine, phenethylamine andphenylpropylamine; salts of 5- or 6-membered heterocyclic compoundscontaining in its ring structure one or two nitrogen atoms as theheteroatom such as piperidine, piperazine, imidazoline and pyrrole;salts of mono-, di- or trialkanolamines such as monoethanolamine,monopropanolamine, diethanolamine and triethanolamine; salts of basicamino acids such as lysine, arginine and histidine; organic amines suchas tris(hydroxymethyl)aminomethane; etc.

Of the compounds of the formula (I), preferable are the compounds inwhich R₁ is hydrogen, methyl, isopropyl or halogen, R₂ is hydrogen ormethyl, R₃ is 3,4-dichlorobenzyl, 2,4-dichlorobenzyl or4-bromo-2-fluorobenzyl, and Z is oxygen or sulfur. Most preferable arethe compounds of the formula (I) in which R₁ is isopropyl, chlorine orbromine, R₂ is hydrogen, R₃ is 4-bromo-2-fluorobenzyl, and Z is oxygen.

The compounds of the present invention of the formula (I) and thepharmaceutically acceptable salts thereof display excellentaldose-reductase inhibitory effects and are useful as a medicament,especially for treating chronic syndromes and complications due todiabetes.

Therefore, the present invention provides an aldose-reductase inhibitorcontaining an effective amount of the compound of the formula (I) or apharmaceutically acceptable salt thereof and a pharmacological carrier.

The present invention also provides a method of inhibitingaldose-reductase comprising administrating to patients an effectiveamount of the compound of the formula (I) or a pharmaceuticallyacceptable salt thereof.

The thienopyrimidine derivative of the present invention of the formula(I) in which Z is oxygen can be prepared by the process as shown belowin Reaction scheme (1). When one or both of R₁ and R₂ in the aboveformula (I) are halogen, the compound can be prepared by the process asshowm below in Reaction scheme (1) or (2). The compound of the formula(I) wherein Z is sulfur can be prepared by the process as shown below inReaction scheme (3). ##STR6##

In the foregoing formulas, R₁, R₂ and R₃ are as defined above, and R₇ isa carboxyl-protecting group.

The compound of the formula (II) is known and described, for example, in"Heterocyclic Compounds", vol. 44. part 3, pp 565-973 "Thiophene and itsderivatives", written by John M. Barker and Patrick R. Huddleston,edited by Salo Gronowitz, published by John Wiley & Sons, Inc., New York(1986).

Generally used as carboxyl-protecting groups represented by R₇ are knowngroups, for example, subtituted or unsubstituted alkyl groups such asmethyl, ethyl, propyl, butyl, tert-butyl and trichloroethyl; substitutedor unsubstituted aralkyl groups such as benzyl, diphenylmethyl,p-nitrobenzyl and p-methoxybenzyl; acyloxyalkyl groups such asacetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxymethyl,pivaloyloxypropyl, benzoyloxymethyl, benzoyloxyethyl,benzylcarbonyloxymethyl and cyclohexylcarbonyloxymethyl; alkoxyalkylgroups such as methoxymethyl, ethoxymethyl and benzyloxymethyl; andother groups such as tetrahydropyranyl, dimethylaminoethyl,dimethylchlorosilyl and trichlorosilyl.

Each step in the above scheme can be done as described below in moredetail.

Step A

The thiophene derivative of the formula (II) is allowed to react with anamine of the formula

    R.sub.3 NH.sub.2                                           (V)

(in which R₃ is as defined above) in the presence or absence of a basein a suitable solvent, giving the thienopyrimidine derivative of theformula (III).

Examples of the amine of the formula (V) are methylamine, ethylamine,propylamine, isopropylamine, pentylamine, hexylamine, benzylamine,4-chlorobenzylamine, 2,4-dichlorobenzylamine, 3,4-dichlorobenzylamine,4-methoxybenzylamine, 4-methylbenzylamine, 2-fluoro-4-bromobenzylamine,2,4-difluorobenzylamine, etc. Although the solvent is not specificallylimited insofar as it does not participate in this reaction, it ispreferred to use alcohols such as methanol, ethanol, propanol andisopropanol; N,N-dimethylformamide; N,N-acetylacetamide; ethers such astetrahydrofuran and dioxane; or the mixture of these solvents. Examplesof bases useful in this reaction are alkoxides of alkali metals oralkaline earth metals such as sodium methoxide, potassium methoxide,potassium t-butoxide, sodium ethoxide, sodium isopropoxide and magnesiummethoxid; hydrides such as sodium hydride, potassium hydride and lithiumhydride; amide compounds such as lithium diisopropylamide, lithiumdicyclohexylamide, sodium amide and potassium amide; organic bases suchas triethylamine, 4-(N,N-dimethylamino)pyridine and hydroxypyridine;etc. The base is preferably used in an amount of about 1.0-1.5 moles permole of the amine (V). Although the proportions of the thiophenederivative (II) and the amine (V) may be appropriately determined, ingeneral the amine (V) is preferably used in an amount of about 1.0-2.0moles per mole of the thiophene derivative (II). The reaction is usuallyconducted with heating at a temperatuare of about 60°-300° C.,preferably at a temperature of about 200°-250° C.

Step B

The thienopyrimidine derivative of the formula (III) is allowed to reactwith an acetic acid derivative of the formula

    XCH.sub.2 COOR.sub.7                                       (VI)

(in which R₇ is as defined above, and X is chlorine, bromine or iodine)in the presence of a base in a suitable solvent, giving thethienopyrimidine acetate derivative of the formula (IV). Although thesolvent is not specifically limited insofar as it does not participatein this reaction, it is preferred to use ethers such as diethyl ether,tetrahydrofuran, dimethoxyethane and dioxane, aromatic hydrocarbons suchas benzene, toluene and xylene, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide or the like.

Examples of useful bases are alkoxides of alkali metals or alkalineearth metals such as potassium methoxide, potassium ethoxide, potassiumt-butoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodiumisopropoxide, lithium methoxide and magnesium ethoxide; hydrides such aspotassium hydride, sodium hydride and lithium hydride; amide compoundssuch as sodium amide, lithium amide, potassium amide and lithiumdiisopropylamide; hydroxides such as potassium hydroxide, sodiumhydroxide, lithium hydroxide and calcium hydroxide; carbonates such aspotassium carbonate and sodium carbonate; etc. The base is preferablyused in an amount of about 1.0-1.5 moles per mole of the acetic acidderivative (VI). Although the proportions of the thienopyrimidinederivative (III) and the acetic acid derivative (VI) can beappropriately determined, in general the acetic acid derivative (VI) ispreferably used in an amount of about 1.0-2.0 moles per mole of thethienopyrimidine derivative (III). Although the reaction temperature isnot specifically limited, the reaction is usually conducted with coolingor at room temperature.

Step C

The thienopyrimidine acetate derivative of the formula (IV) obtained issubjected to de-esterification reaction with or without isolation fromthe reaction system of Step B, giving the thienopyrimidine derivative ofthe formula (I). The de-esterification is conducted by a conventionalmethod, for example, by a method using acid or base, etc.

Examples of acids useful in a method using acid are lower fatty acidssuch as formic acid, acetic acid and propionic acid, trihaloacetic acidssuch as trichloroacetic acid and trifluoroacetic acid, halogenatedhydroacids such as hydrochloric acid, hydrobromic acid and hydrofluoricacid, organic sulfonic acids such as p-toluenesulfonic acid andtrifluoromethanesulfonic acid; and mixtures thereof.

When an acid in the liquid form is used in the above reaction with anacid, no other solvent is required, but a solvent which does notparticipate in the reaction can be used, for example, halogenatedhydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane,cyclic ethers such as tetrahydrofuran and dioxane,N,N-dimethylformamide, acetone, water and mixtures thereof.

Examples of bases useful in a method using a base are hydroxides ofalkali metals or alkaline earth metals such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide andmagnesium hydroxide, carbonates such as potassium carbonate and sodiumcarbonate, 1,8-diazabicyclo[5,4,0]-7-undecene, etc. As a solvent, thosewhich do not participate in the reaction are used, for example, alcoholssuch as methanol, ethanol and isopropanol, ethers such astetrahydrofuran, dimethoxyethane and dioxane, N,N-dimethylformamide,mixtures of the aforementioned solvents and/or water, etc.

In the above Reaction scheme (1), the compound (III) can be alsosynthesized from the thiophene derivative of the formula (II') by theprocess as shown in the following reaction scheme. ##STR7##

In the foregoing formulas, R₁, R₂ and R₃ are as defined above.

The compound of the formula (II') is knowm and described, for example,in "Heterocyclic Compounds", vol. 44. part 3, pp 565-973 "Thiophene andits derivatives", written by John M. Barker and Patrick R. Huddleston,edited by Salo Gronowitz, published by John Wiley & Sons, Inc., New York(1986).

The thiophene derivative of the formula (II') is heated to 50°-120° C.in the presence of phosgene or trichloromethyl chloroformate in asuitable solvent, and then the solvent is distilled off, giving theisocyanate derivative (II"). Examples of useful solvents are aromatichydrocarbons such as xylene, toluene and benzene, halogenatedhydrocarbons such as chloroform, 1,2-dichloroethane andtetrachloromethane, esters such as ethyl acetate and isopropyl acetate,cyclic ethers such as dioxane and tetrahydrofuran, dimethoxyethane andlike solvents which do not participate in the reaction. The compound(II") is allowed to react with the amine of formula (V) in a solvent,giving the ureide derivative (II"'). Solvents suitable for the reactionare ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran anddioxane, aromatic hydrocarbons such as xylene, toluene, benzene andchlorobenzene, halogenated hydrocarbons such as chloroform,1,2-dichloroethane, tetrachloromethane and dichloromethane, etc.Although the reaction usually proceeds exothermically at roomtemperature, at the conclusion of the reaction the reaction system maybe heated or such as a base may be as 4-(N,N-dimethylamino)pyridine,pyridine, triethylamine, N-methylpiperidine, diisopropylethylamine,dicyclohexylethylamine, etc. The base is used in an amount of 0.1-3.0equivalents per equivalent of the amine (V). The amount of the amine (V)is appropriately determined, but it is usually preferable to use theamine (V) in an amount of about 1.0 to about 2.0 moles per mole of thethiophene derivative (II"). The resulting ureide derivative (II"') issubjected to cyclization in a suitable solvent as it is or in thepresence of a base, giving the thienopyrimidine derivative of theformula (III). As a base are exemplified organic amines such astriethylamine, pyridine, N-methylpiperidine, diisopropylethylamine anddicyclohexylethylamine, hydroxides of alkali metals such as sodiumhydroxide and potassium hydroxide, alkoxides of alkali metals such assodium methoxide, sodium ethoxide, sodium isopropoxide, potassiummethoxide, potassium ethoxide, potassium t-butoxide and lithiummethoxide, hydrides of alkali metals such as potassium hydride, lithiumhydride and sodium hydride and other usual bases. Suitably used as asolvent are alcohols such as methanol, ethanol, propanol, isopropanoland butanol, ethers such as tetrahydrofuran, dimethoxyethane anddioxane, amides such as N,N-dimethylformamide and N,N-dimethylacetamide,dimethylsulfoxide or mixtures thereof. The base is preferably used in anamount of about 1.0-3.0 moles per mole of the ureide derivative. Thereaction is carried out usually at a temperature of about 50° to about150° C. ##STR8##

In the foregoing formulas, R₁ ' and R₂ ' are the same as R₁ and R₂provided that at least one of them is hydrogen, R₇ ' is hydrogen or thesame as R₇, R₁ " and R₂ " and the same as R₁ and R₂ provided that atleast one of them is halogen, and R₃ and R₇ are as defined above.

Step D

The compound of the formula (IV') in which one or two hydrogen atomsexist in the thiophene ring moiety of the compound (IV) can behalogenated at the thiophene ring by a conventional method generallyused in halogenating a thiophene. This procedure gives the compound ofthe formula (IV") or (I) in which one or two halogen atoms exist in thethiophene ring moiety. The halogenation is conducted by causing such ahalogenating agent to act as chlorine, sulfuryl chloride, bromine andiodine in the presence or the absence of a catalyst in a solvent whichdoes not participate in the reaction. Suitable solvents include aceticacid, ethers such as ethyl ether and dioxane, halogenated hydrocarbonssuch as chloroform, 1,2-dichloroethane, tetrachloromethane anddichloromethane, water or mixtures thereof. In this case, the reactiontemperature is not limited specifically. Examples of catalysts areinorganic acids such as sulfuric acid and periodic acid, Lewis acidssuch as alminium chloride, mercury chloride and tin chloride and thelike. The halogenation is also suitably carried out by reacting thecompound (IV') with a N-halogenosuccinimide such as N-chlorosuccinimideor N-bromosuccinimide as a halogenating agent in the above solvent at atemperature between room temperature and the reflux temperature of thesolvent. The halogenating agent is generally used in an amount of about1.0 to about 2.5 moles per mole of the compound (IV'). The compound ofthe formula (IV") can be made into the compound (I) by the method atStep C in Reaction scheme (1). ##STR9##

In the foregoing formulas, R₁, R₂, R₃ and R₇ are as defined above.

Step E

One to two equivalents of sodium hydride is added to a solution of thecompound of the formula (VII) in N,N-dimethylformamide at a temperatureof below room temperature, and the mixture is allowed to react with theacetic acid derivative (VI). Then the amine of the formula (V) is addedand the mixture is allowed to react at a temperature between roomtemperature and 100° C. to obtain the compound of the formula (VIII).The compounds of the formulas (VI) and (V) are preferably used inamounts of about 1.0 to about 2.0 moles per mole of the compound (VII).

The compound of the formula (VII) can be prepared according to aconventional method for preparing isatonic anhydride by reacting theknown corresponding 2-amino-3-thiophenecarboxylic acid ("HeterocyclicCompounds" vol. 44. part 3, pp 565-973 "Thiophene and its derivatives",written by John M. Barker and Patrick R. Huddleston, edited by SaloGronowitz, published by John Wiley & Sons, Inc., New York (1986)) withphosgene or trichloromethyl chloroformate. The method using phosgene isdescribed, for example, in E. C. Wagner and M. F. Fegley. OrganicSynthesis, vol. III, 488 (1955). The method using trichloromethylchloroformate is described, for example, in K. Kurita, T. Matsumura andY. Iwakura, Journal of Organic Chemistry, vol. 41, 2070 (1976).

Step F

One mole of the compound of the formula (VIII) and 2 to 3 moles of1,1'-thiocarbonyldiimidazole are dissolved in dioxane. The solution isheated to a bath temperature of 150° C. and allowed to react for one tofour hours, giving the thienopyrimidine derivative of the formula(IV"'). The compound can be treated in the same manner as in Step C inReaction scheme (1) to give a compound of the formula (I).

The novel thienopyrimidine derivative of the present invention producedby the above reaction can be easily isolated by a conventionalseparation method, for example, recrystallization, column chromatographyor the like.

For use in preventing or treating the diseases caused byaldose-reductase, e.g., diabetic cataract, neuropathy, nephropathy,diabetic retinopathy, the thienopyrimidine derivatives of the presentinvention are administered to mammals including humans in any ofpharmaceutical dosage forms including oral preparation, injection,suppository and eye drop. Such preparations can be formulated in amanner already known in the art.

For the formulation of solid preparations for oral administration suchas tablets, coated tablets, granules, powders and capsules, an excipientand, when required, a binder, disintegrator, lubricant, coloring agent,corrigent, flavor, etc. are added to the compound of the invention, andthen a preparation is formulated in a usual manner. Such additives arethose already known in the art, and usuful examples are excipients suchas lactose, sucrose, sodium chloride, glucose solution, starch, calciumcarbonate, kaolin, crystalline cellulose and silicic acid; binders suchas water, ethanol, propanol, glucose, carboxymethyl cellulose,hydroxymethyl cellulose, methyl cellulose, ethyl cellulose, schellac,potassium phosphate and polyvinyl pyrrolidone; disintegrators such asdried starch, sodium alginate, agar powder, sodium hydrogencarbonate,calcium carbonate, sodium lauryl sulfate, glyceryl monostearate andlactose; lubricants such as purified talc, stearic acid salt, boric acidpowder and polyethylene glycol; corrigents such as sucrose, orange peel,citric acid and tartaric acid, etc.

For the formulation of liquid preparations for oral administration suchas oral liquid preparations and syrups, a corrigent, buffer, stabilizer,flavor, etc. can be added to the compound of the present invention,whereafter a preparation can be formulated in a usual manner. Examplesof useful corrigents are those exemplified above. Examples of buffersare sodium citrate, etc. Examples of stabilizers are tragacanth, gumarabic, gelatin, etc.

Parenteral preparations such as a subcutaneous injection, intramuscularinjection, intravenous injection or the like can be prepared in a usualmanner by adding to the comopound of the invention a pH adjusting agent,buffer, stabilizer, isotonic agent, local anesthetic, etc. Examples ofpH adjusting agents and buffers are sodium citrate, sodium acetate,sodium phosphate, etc. Examples of stabilizers are sodium pyrosulfite,EDTA, thioglycolic acid, thiolactic acid, etc. Examples of localanesthetics are procaine hydrochloride, lidocaine hydrochloride, etc.

Suppositories can be prepared in a usual manner by adding excipientssuch as unsaturated fatty acid triglycerides and, if required,surfactants such as Tween.

Eye drops can be prepared in a usual manner by using a diluent such asdistilled water and physiological saline. Eye drops should preferably bemade isotonic by using a pH adjusting agent, buffer, etc.

The amount of the compound of the present invention to be incorporatedinto each dosage form varies with the symptoms of the patient or withthe type of the preparation. Preferably the amount per administrationunit is about 10 to about 300 mg for oral administration, about 10 toabout 50 mg for pareteral administration, about 10 to 200 mg forintrarectal administration and about 5 to about 50 mg for administrationto eyes. The dosage per day of such preparations is variable with thesymptoms, body weight, age, sex and the like of the patient. Usually thepreparation is adminstered to an adult in an amount of about 5 to about900 mg per day based on the compound, preferably in one or two to fourdevided doses.

The present invention will be described below in more detail withreference to Reference Examples and Examples.

REFERENCE EXAMPLE 1 Preparation of3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(Compound III-1)

A 1 g quantity of ethyl2-ethoxycarbonylamino-4,5-dimethyl-3-thiophenecarboxylate and 1 g of4-chlorobenzylamine were dissolved in a mixture of 3 ml of ethanol and 1ml of N,N-dimethylformamide and the mixture was allowed to react in asealed tube at 230° C. for 7 hours. The reaction mixture wasconcentrated and the residue was recrystallized from anacetone-ethanol-dimethylformamide mixture, giving 0.8 g of3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dionehaving a melting point of 291° to 292° C. in a yield of 68%.

    ______________________________________                                        Elemental Analysis (for C.sub.15 H.sub.13 N.sub.2 O.sub.2 SCl)                         C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              56.16        4.08   8.73                                           Found (%): 56.12        4.00   8.83                                           ______________________________________                                    

REFERENCE EXAMPLE 2

The compounds III-2 to III-9 as shown below in Table 1 were prepared inthe same manner as in Reference Example 1.

REFERENCE EXAMPLE 3 Preparation of3-(4-bromo-2-fluorobenzyl)-5-methylthieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione(Compound III-17)

A solution of 3.71 g of ethyl 2-amino-4-methyl-3-thiophenecarboxylateand 7.91 g of trichloromethyl chloroformate in 50 ml of dioxane wasstirred at a bath temperature of 80° to 100° C. for 3 hours, and thesolvent was evaporated off under reduced pressure. The residue wasdissolved in 30 ml of diethyl ether and 4.49 g of4-bromo-2-fluorobenzylamine was added dropwise thereto with ice-cooling.After the temperature of the mixture was raised to room temperature, themixture was stirred for three hours, 20 ml of n-hexane was addeddropwise thereto and a colorless precipitate was collected, giving 5.4 gof the ureide compound of the following formula in a yield of 68%.##STR10##

A 5.3 g quantity of the ureide compound was dissolved in 70 ml ofethanol and 1.58 g of sodium methoxide was added thereto. The mixturewas refluxed for 5 hours, concentrated to a half of volume, and thenhomogeneously mixed with 20 ml of water. The resulting solution wasneutralized and acidified with concentrated hydrochloric acid toprecipitate colorless crystals. The crystals were collected byfiltration, washed with water and dried in vacuo, giving 4.75 g of thecompound III-17 having a melting point of 296° to 297.5° C. in a yieldof 97%.

    ______________________________________                                        Elemental Analysis (for C.sub.14 H.sub.10 N.sub.2 O.sub.2 SBrF)                        C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              45.54        2.73   7.59                                           Found (%): 45.51        2.61   7.64                                           ______________________________________                                    

REFERENCE EXAMPLE 4

The compounds III-10 to III-16, III-18 and III-19 as shown below inTable 1 were prepared in the same manner as in Reference Example 3.

                                      TABLE 1                                     __________________________________________________________________________     ##STR11##                                                                    __________________________________________________________________________    Compound No.                                                                          R.sub.1                                                                             R.sub.2                                                                          R.sub.3      Yield (%)                                                                           mp (°C.)                           __________________________________________________________________________    III-1   CH.sub.3                                                                            CH.sub.3                                                                          ##STR12##   68    291˜292                             III-2   CH.sub.3                                                                            CH.sub.3                                                                          ##STR13##   70    275˜276                             III-3   (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR14##   43    252.5˜ 253.5                        III-4   (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR15##   12    223˜226                             III-5   H     CH.sub.3                                                                          ##STR16##   70    299˜300                             III-6                                                                                  ##STR17##                                                                              ##STR18##   29    230˜232                             III-7                                                                                  ##STR19##                                                                              ##STR20##   40    240˜241                             III-8                                                                                  ##STR21##                                                                              ##STR22##   45    255˜256                             III-9                                                                                  ##STR23##                                                                             (CH.sub.2).sub.5 CH.sub.3                                                                  24    132˜ 132.5                          III-10  CH.sub.3                                                                            H                                                                                 ##STR24##   55    304˜305                             III-11  CH.sub.3                                                                            CH.sub.3                                                                          ##STR25##   47    258˜ 258.5                          III-12                                                                                 ##STR26##                                                                              ##STR27##   49    225˜230                             III-13                                                                                 ##STR28##                                                                          H                                                                                 ##STR29##   69    257˜259                             III-14  (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR30##   76    227˜228                             III-15  (CH.sub.3).sub.3 C                                                                  H                                                                                 ##STR31##   43    263.5˜ 265                          III-16  H     H                                                                                 ##STR32##   71    290˜291                             III-17  H     CH.sub.3                                                                          ##STR33##   66    296˜ 297.5                          III-18  (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR34##   64    219˜221                             III-19                                                                                 ##STR35##                                                                          H                                                                                 ##STR36##   50    257˜259                             __________________________________________________________________________                          Elemental Analysis(%): Calcd. in parenthesis            Compound No.                                                                            Molecular Formula                                                                       C       H   N                                             __________________________________________________________________________    III-1     C.sub.15 H.sub. 13 N.sub.2 O.sub.2 ClS                                                  (56.16) (4.08)                                                                            (8.73)                                                            56.12   4.00                                                                              8.83                                          III-2     C.sub.15 H.sub.12 N.sub.2 O.sub.2 Cl.sub.2 S                                            (50.72) (3.40)                                                                            (7.89)                                                            50.43   3.26                                                                              7.80                                          III-3     C.sub.16 H.sub.14 N.sub.2 O.sub.2 Cl.sub.2 S                                            (52.04) (3.83)                                                                            (7.59)                                                            52.01   3.87                                                                              7.60                                          III-4     C.sub.16 H.sub.14 N.sub.2 O.sub.2 Cl.sub.2 S                                            (52.04) (3.83)                                                                            (7.59)                                                            51.75   3.81                                                                              7.51                                          III-5     C.sub.14 H.sub.10 N.sub.2 O.sub.4 S                                                     (62.21) (3.73)                                                                            (10.36)                                                           62.10   3.54                                                                              10.20                                         III-6     C.sub.18 H.sub.18 N.sub.2 O.sub.3 S                                                     (63.14) (5.30)                                                                            (8.18)                                                            63.28   5.11                                                                              8.17                                          III-7     C.sub.18 H.sub.18 N.sub.2 O.sub.2 S                                                     (66.23) (5.56)                                                                            (8.58)                                                            66.30   5.42                                                                              8.50                                          III-8     C.sub.17 H.sub.14 Cl.sub.2 N.sub.2 O.sub.2 S                                            (53.55) (3.70)                                                                            (7.35)                                                            53.45   3.77                                                                              7.37                                          III-9     C.sub.16 H.sub.22 N.sub.2 O.sub.2 S                                                     (62.72) (7.24)                                                                            (9.14)                                                            62.50   7.12                                                                              9.02                                          III-10    C.sub.14 H.sub.10 BrFN.sub.2 O.sub.2 S                                                  (45.54) (2.73)                                                                            (7.59)                                                            45.86   3.04                                                                              7.51                                          III-11    C.sub.15 H.sub.12 BrFN.sub.2 O.sub.2 S                                                  (47.01) (3.16)                                                                            (7.31)                                                            47.11   3.18                                                                              7.41                                          III-12    C.sub.17 H.sub.14 FBrN.sub.2 O.sub.2 S                                                  (49.89) (3.45)                                                                            (6.84)                                                            49.49   3.20                                                                              6.76                                          III-13    C.sub.18 H.sub.16 BrFN.sub.2 O.sub.2 S                                                  (51.07) (3.81)                                                                            (6.62)                                                            50.86   3.84                                                                              6.63                                          III-14    C.sub.16 H.sub.14 BrFN.sub.2 O.sub.2 S                                                  (48.38) (3.55)                                                                            (7.05)                                                            48.18   3.56                                                                              7.11                                          III-15    C.sub.17 H.sub.16 Cl.sub.2 N.sub.2 O.sub.2 S                                            (53.27) (4.21)                                                                            (7.31)                                                            53.58   4.37                                                                              7.31                                          III-16    C.sub.13 H.sub.8 BrFN.sub.2 O.sub.2 S                                                   (43.96) (2.27)                                                                            (7.89)                                                            44.05   2.30                                                                              7.83                                          III-17    C.sub.14 H.sub.10 BrFN.sub.2 O.sub.2 S                                                  (45.54) (2.73)                                                                            (7.59)                                                            45.51   2.61                                                                              7.64                                          III-18    C.sub.16 H.sub.14 F.sub.2 N.sub.2 O.sub.2 S                                             (57.13) (4.20)                                                                            (8.33)                                                            57.63   4.42                                                                              8.53                                          III-19    C.sub.16 H.sub.18 Cl.sub.2 N.sub.2 O.sub.2 S                                            (54.69) (4.08)                                                                            (7.09)                                                            54.70   4.18                                                                              6.99                                          __________________________________________________________________________

REFERENCE EXAMPLE 5 Preparation of3-(4-chlorobenzyl)-1-ethoxycarbonylmethyl-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(Compound IV-1)

A 0.6 g quantity of3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(Compound III-1) was dissolved in 20 ml of anhydrousN,N-dimethylformamide. To the solution were added at room temperature0.1 g of 50% sodium hydride and then 0.4 g of ethyl bromoacetate. Themixture was stirred at room temperature for 17 hours, concentrated andacidified by adding diluted hydrochloric acid with ice-cooling. Thecrystals precipitated were collected by filtration and recrystallizedfrom ethanol, giving 0.7 g of3-(4-chlorobenzyl)-1-ethoxycarbonylmethyl-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dionehaving a melting point of 151° to 152° C. in a yield of 92%.

    ______________________________________                                        Elemental Analysis (for C.sub.19 H.sub.19 N.sub.2 O.sub.4 SCl)                         C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              56.09        4.71   6.88                                           Found (%): 55.84        4.50   6.89                                           ______________________________________                                    

REFERENCE EXAMPLE 6

The compounds IV-2 to IV-8 and IV-12 to IV-22 as shown below in Table 2were prepared in the same manner as in Reference Example 5.

REFERENCE EXAMPLE 7 Preparation of1-ethoxycarbonylmethyl-3-hexyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(Compound IV-9)

A 1.2 g quantity of3-hexyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(Compound III-9), 0.14 g of 50% sodium hydride and 1.0 g of ethylbromoacetate were allowed to react with each other in the same manner asin Reference Example 5. The residue obtained by concentration wassubjected to silica gel column chromatography using chloroform as aneluent. Then 1.2 g of1-ethoxycarbonylmethyl-3-hexyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-2,4(1H,3H)-dionewas obtained in a yield of 77%.

Nuclear Magnetic Resonance (DMSO-d₆): δ(ppm): 0.85 (3H, t), 1.0-2.0(12H, m), 1.21 (3H, t), 2.5-2.9 (4H, m), 3.84 (2H, t), 4.17 (2H, q), 4.7(2H, s)

REFERENCE EXAMPLE 8 Preparation of1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-bromo-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(Compound IV"-10)

A 0.3 g quantity of1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(compound IV-5) synthesized in Reference Example 6 and 0.137 g ofN-bromosuccinimide were dissolved in 30 ml of anhydroustetrachloromethane, and the mixture was refluxed for 2 hours. Thesolvent was distilled off under reduced pressure and the residual solidobtained was purified by silica gel column chromatography(eluent:chloroform:n-hexane=2:1) to afford 0.30 g of1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-bromo-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dionehaving m.p. of 165.5° to 167° C. in a yield of 85%.

    ______________________________________                                        Elemental Analysis (for C.sub.18 H.sub.15 N.sub.2 O.sub.4 SBrCl.sub.2)                 C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              47.21        2.99   5.53                                           Found (%): 47.50        2.84   5.42                                           ______________________________________                                    

REFERENCE EXAMPLE 9

The compound IV"-23 as shown in Table 2 was prepared in the same manneras in Reference Example 8.

REFERENCE EXAMPLE 10 Preparation of1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(Compound IV"-11)

A 0.427 g quantity of1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(compound IV-5) synthesized in Reference Example 6 and 0.162 g ofsulfuryl chloride were dissolved in 30 ml of anhydroustetrachloromethane, and the mixture was allowed to react at 50° to 70°C. for 6 hours. The residue obtained by concentration of the reactionmixture was subjected to silica gel column chromatography using a 2:1mixture of chroloform and n-hexane as an eluent to afford 0.30 g of1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dionehaving m.p. of 141° to 145° C. in a yield of 65%.

    ______________________________________                                        Elemental Analysis (for C.sub.18 H.sub.15 N.sub.2 O.sub.4 SCl.sub.3)                   C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              46.82        3.27   6.07                                           Found (%): 46.65        3.12   5.92                                           ______________________________________                                    

REFERENCE EXAMPLE 11

The compound IV"-24 as shown in Table 2 was prepared in the same manneras in Reference Example 10.

REFERENCE EXAMPLE 12 Preparation of1-ethoxycarbonylmethyl-3-(4-bromo-2-fluorobenzyl)-6-isopropyl-4(3H)-oxo-2(1H)-thioxothieno[2,3-d]pyrimidine(Compound IV"'-25)

A 7.8 g quantity of 2-amino-5-isopropylthiophenecarboxylic acid and 25 gof trichloromethyl chloroformate were dissolved in 80 ml of dioxane. Theresulting solution was refluxed for 6 hours and then the solvent wasevaporated off under reduced pressure. The pale brown solids obtainedwere crushed in ether and the pieces were collected by filtration anddried in vacuo. As pale color solids was obtained 5.6 g of the compoundof the following formula in a yield of 74%. ##STR37##

M.p.: 180°-181° C. (CO₂ generated).

    ______________________________________                                        Elemental Analysis (for C.sub.9 H.sub.9 NO.sub.3 S)                                    C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              51.17        4.29   6.63                                           Found (%): 51.21        4.36   6.65                                           ______________________________________                                    

A 5.4 g quantity of this compound was dissolved in 40 ml ofN,N-dimethylformamide and 1.45 g of 60% sodium hydride was added to thesolution with ice-cooling. After stirring for 40 minutes, 4.34 ml ofethyl bromoacetate was added thereto. The temperature of the mixture wasraised to room temperature, and the reaction was conducted for 2 hours.Then 7.96 g of 4-bromo-2-fluorobenzylamine was added to the reactionmixture, the mixture was allowed to react at 80° C. for two hours, 5.4ml of triethylamine was added thereto and the reaction mixture wasallowed to react for 1 hour. The solvent was distilled off under reducedpressure and the residue was extracted with 120 ml of chloroform. Theextract was washed with water, dried over anhydrous sodium carbonate andthen concentrated. The residue obtained was recrystallized from amixture of chloroform, iropropyl ether and n-hexane, giving 8.92 g ofthe compound of the following formula as pale yellow needle crystals ina yield of 65%. ##STR38##

M.p.: 135.5°-137.5° C.

    ______________________________________                                        Elemental Analysis (for C.sub.19 H.sub.22 N.sub.2 O.sub.3 SBrF)                        C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              49.90        4.85   6.13                                           Found (%): 49.63        4.65   6.16                                           ______________________________________                                    

A 2.29 quantity of this compound and 1.96 g of1,1'-thiocarbonyldiimidazole were dissolved in 20 ml of dioxane. Thedioxane was distilled off with stirring on the bath at 150° C. and themixture was allowed to react for 2 hours. Ethanol was added to thereaction mixture when hot and the solution was cooled to roomtemperature. The crystals precipitated were collected and purified bysilica gel (75 g) column chromatography using chloroform as an eluent,giving as colorless crystals 2.11 g of Compound IV"'-25 having m.p. of177° to 179° C. in a yield of 85%.

    ______________________________________                                        Elemental Analysis (for C.sub.20 H.sub.20 N.sub.2 O.sub.3 S.sub.2 BrF)                 C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              48.10        4.04   5.61                                           Found (%): 48.30        3.94   5.64                                           ______________________________________                                    

                                      TABLE 2                                     __________________________________________________________________________     ##STR39##                                (IV)                                __________________________________________________________________________    Compound No.                                                                          R.sub.1                                                                             R.sub.2                                                                          R.sub.3      Z R.sub.7                                                                          Yield (%)                                                                           mp (°C.)                      __________________________________________________________________________    IV-1    CH.sub.3                                                                            CH.sub.3                                                                          ##STR40##   O C.sub.2 H.sub.5                                                                  92    151˜152                        IV-2    CH.sub.3                                                                            CH.sub.3                                                                          ##STR41##   O C.sub.2 H.sub.5                                                                  96    150˜151                        IV-3    (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR42##   O C.sub.2 H.sub.5                                                                  89    91˜92                          IV-4    (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR43##   O C.sub.2 H.sub.5                                                                  61    146˜148                        IV-5    H     CH.sub.3                                                                          ##STR44##   O C.sub.2 H.sub.5                                                                  46    124˜126                        IV-6                                                                                   ##STR45##                                                                              ##STR46##   O C.sub.2 H.sub.5                                                                  60    153.5˜ 154                     IV-7                                                                                   ##STR47##                                                                              ##STR48##   O C.sub.2 H.sub.5                                                                  65    147˜149                        IV-8                                                                                   ##STR49##                                                                              ##STR50##   O C.sub.2 H.sub.5                                                                  66    169˜170                        IV-9                                                                                   ##STR51##                                                                             (CH.sub.2).sub.5 CH.sub.3                                                                  O C.sub.2 H.sub.5                                                                  77    Oil                                  IV"-10  Br    CH.sub.3                                                                          ##STR52##   O C.sub.2 H.sub.5                                                                  85    165.5˜ 167                     IV"-11  Cl    CH.sub.3                                                                          ##STR53##   O C.sub.2 H.sub.5                                                                  65    141˜145                        IV-12   CH.sub.3                                                                            H                                                                                 ##STR54##   O C.sub.2 H.sub.5                                                                  58    145˜147                        IV-13                                                                                  ##STR55##                                                                          H                                                                                 ##STR56##   O C.sub.2 H.sub.5                                                                  70    234˜235                        IV-14   CH.sub.3                                                                            CH.sub.3                                                                          ##STR57##   O C.sub.2 H.sub.5                                                                  88    144˜146                        IV-15                                                                                  ##STR58##                                                                              ##STR59##   O C.sub.2 H.sub.5                                                                  60    141˜143                        IV-16                                                                                  ##STR60##                                                                          H                                                                                 ##STR61##   O C.sub.2 H.sub.5                                                                  83    96˜97                          IV-17   (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR62##   O C.sub.2 H.sub.5                                                                  88    99˜101                         IV-18   (CH.sub.3).sub.3 C                                                                  H                                                                                 ##STR63##   O C.sub.2 H.sub.5                                                                  68    115˜116                        IV-19   H     H                                                                                 ##STR64##   O C.sub.2 H.sub.5                                                                  63    117˜119                        IV-20   H     CH.sub.3                                                                          ##STR65##   O C.sub.2 H.sub.5                                                                  87    153˜154                        IV-21   (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR66##   O C.sub.2 H.sub.5                                                                  50    111˜112                        IV-22                                                                                  ##STR67##                                                                          H                                                                                 ##STR68##   O C.sub.2 H.sub.5                                                                  73    135˜136                        IV"-23  Br    H                                                                                 ##STR69##   O C.sub.2 H.sub.5                                                                  62    169˜170                        IV"-24  Cl    H                                                                                 ##STR70##   O C.sub.2 H.sub.5                                                                  93    132.5˜ 133.5                   IV"'-25 (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR71##   S C.sub.2 H.sub.5                                                                  85    177˜179                        __________________________________________________________________________                         Elemental Analysis(%): Calcd. in parenthesis             Compound No.                                                                            Molecular Formula                                                                        C       H        N                                       __________________________________________________________________________    IV-1      C.sub.19 H.sub.19 N.sub.2 O.sub.4 ClS                                                    (56.09) (4.71)   (6.88)                                                       55.84   4.50     6.89                                    IV-2      C.sub.19 H.sub.18 N.sub.2 O.sub.4 Cl.sub.2 S                                             (51.71) (4.11)   (6.35)                                                       51.42   4.19     6.14                                    IV-3      C.sub.20 H.sub.20 N.sub.2 O.sub.4 Cl.sub.2 S                                             (52.75) (4.43)   (6.15)                                                       52.85   4.45     6.15                                    IV-4      C.sub.20 H.sub.20 N.sub.2 O.sub.4 Cl.sub.2 S                                             (52.75) (4.43)   (6.15)                                                       52.86   4.44     6.11                                    IV-5      C.sub.18 H.sub.16 N.sub.2 O.sub.4 Cl.sub.2 S                                             (50.60) (3.77)   (6.56)                                                       50.70   3.77     6.62                                    IV-6      CHN.sub.2 O.sub.5 S                                                                      (61.67) (5.65)   (6.54)                                                       61.70   5.77     6.49                                    IV-7      C.sub.22 H.sub.24 N.sub.2 O.sub. 4 S                                                     (64.06) (5.86)   (6.79)                                                       64.14   5.81     6.75                                    IV-8      C.sub.21 H.sub.20 Cl.sub.2 N.sub.2 O.sub.4 S                                             (53.97) (4.31)   (5.99)                                                       53.80   4.32     5.99                                    IV-9      C.sub.20 H.sub.28 N.sub.2 O.sub.4 S                                                      (61.20) (7.19)   (7.14)                                                       60.95   7.38     6.95                                    IV"-10    C.sub.18 H.sub.15 BrCl.sub.2 N.sub.2 O.sub.4 S                                           (47.21) (2.99)   (5.53)                                                       47.50   2.84     5.42                                    IV"-11    C.sub.18 H.sub.15 Cl.sub.3 N.sub.2 O.sub.4 S                                             (46.82) (3.27)   (6.07)                                                       46.65   3.12     5.92                                    IV-12     C.sub.18 H.sub.16 BrFN.sub.2 O.sub.4 S                                                   (47.48) (3.54)   (6.15)                                                       47.35   3.62     6.15                                    IV-13     C.sub.23 H.sub.18 BrFN.sub.2 O.sub.4 S                                                   (53.39) (3.51)   (5.41)                                                       53.57   3.32     5.46                                    IV-14     C.sub.19 H.sub.18 BrFN.sub.2 O.sub.4 S                                                   (48.62) (3.87)   (5.97)                                                       48.48   3.85     5.96                                    IV-15     C.sub.21 H.sub.20 BrFN.sub.2 O.sub.4 S                                                   (50.92) (4.07)   (5.66)                                                       50.70   4.09     5.60                                    IV-16     C.sub.22 H.sub.22 BrFN.sub.2 O.sub.4 S                                                   (51.87) (4.35)   (5.50)                                                       52.35   4.42     5.47                                    IV-17     C.sub.20 H.sub.20 BrFN.sub.2 O.sub.4 S                                                   (49.70) (4.17)   (5.80)                                                       49.77   4.31     5.72                                    IV-18     C.sub. 21 H.sub.22 Cl.sub.2 N.sub.2 O.sub.4 S                                            (53.74) (4.72)   (5.97)                                                       53.70   4.85     6.07                                    IV-19     C.sub.17 H.sub.14 BrFN.sub.2 O.sub.4 S                                                   (46.27) (3.20)   (6.35)                                                       46.35   3.32     6.18                                    IV-20     C.sub.18 H.sub.16 BrFN.sub.2 O.sub.4 S                                                   (47.48) (3.54)   (6.15)                                                       47.50   3.54     6.18                                    IV-21     C.sub.20 H.sub.20 F.sub.2 N.sub.2 O.sub.4 S                                              (56.86) (4.77)   (6.63)                                                       56.46   5.10     6.77                                    IV-22     C.sub.22 H.sub.22 Cl.sub.2 N.sub.2 O.sub.4 S                                             (54.89) (4.61)   (5.82)                                                       55.06   4.56     5.86                                    IV"-23    C.sub.17 H.sub.13 Br.sub.2 FN.sub.2 O.sub.4 S                                            (39.25) (2.52)   (5.39)                                                       39.28   2.60     5.21                                    IV"-24    C.sub.17 H.sub.13 BrClFN.sub.2 O.sub.4 S                                                 (42.92) (2.75)   (5.89)                                                       43.01   2.67     5.91                                    IV"'-25   C.sub.20 H.sub.20 BrFN.sub.2 O.sub.3 S.sub.2                                             (48.10) (4.04)   (5.61)                                                       48.30   3.94     5.64                                    __________________________________________________________________________

EXAMPLE 1 Preparation of1-carboxymethyl-3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (Compound I-1)

A 0.7 g quantity of3-(4-chlorobenzyl)-1-ethoxycarbonylmethyl-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (Compound IV-1) prepared in Reference Example 5 was dissolvedin 30 ml of methanol. To the solution was added 0.3 g of sodiumhydroxide dissolved in 2 ml of water. The mixture was allowed to reactat 60° C. for 30 minutes, and then the reaction mixture wasconcentrated. Diluted hydrochloric acid was added thereto withice-cooling to acidify the resulting solution. The solution wasfiltrated and the separated crystals were recrystallized from methanol,giving 0.4 g of1-carboxymethyl-3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione having m.p. of 173° to 176° C. in a yield of 61%.

    ______________________________________                                        Elemental Analysis (for C.sub.17 H.sub.15 N.sub.2 O.sub.4 SCl)                         C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              53.90        3.99   7.39                                           Found (%): 53.75        4.04   7.31                                           ______________________________________                                    

EXAMPLE 2

The compounds I-2 to I-11 as shown below in Table 3 were prepared in thesame manner as in Example 1.

EXAMPLE 3 Preparation of1-carboxymethyl-3-(4-bromo-2-fluorobenzyl)-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (Compound I-20)

A 4.60 quantity of Compound IV-20 prepared in Reference Example 6, 20 mlof acetic acid and 10 ml of concentrated hydrochloric acid were refluxedfor 4 hours, and then 10 ml of concentrated hydrochloric acid was added.The solution was further refluxed for 4 hours, and 10 ml of water wasadded. The mixture was allowed to stand overnight at room temperature.The crystals precipitated were collected, washed with water andrecrystallized from 80% ethanol, giving 3.75 g of Compound I-20 havingm.p. of 206.5° to 208° C. in a yield of 87%.

    ______________________________________                                        Elemental Analysis (for C.sub.16 H.sub.12 N.sub.2 O.sub.4 SBrF)                        C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              44.98        2.83   6.56                                           Found (%): 45.02        2.78   6.38                                           ______________________________________                                    

EXAMPLE 4

The compounds I-12 to I-19 and I-21 to I-25 as shown below in Table 3were prepared in the same manner as in Example 3.

EXAMPLE 5 Preparation of L-arginine salt of1-carboxymethyl-3-(4-bromo-2-fluorobenzyl)-6-chlorothieno[2,3-d]pyrimidin-2,4(1H,3H)-dione(Compound I-24)

A 0.45 g quantity of Compound I-24 was dissolved in 10 ml of ethanolwith refluxing, and an aqueous solution (1 ml) of 0.174 g of L-argininewas added to the solution. Then the solution was cooled and allowed tostand at room temperature for one day. The crystals precipitated werecollected, washed with ethanol and dried in vacuo at 100° C. for 6hours, giving 0.49 g of the L-arginine salt of Compound I-24 having m.p.of 224° to 225.5° C. in a yield of 76%.

    ______________________________________                                        Elemental Analysis (for C.sub.21 H.sub.23 N.sub.6 O.sub.6 SBrClF)                      C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              40.56        3.73   13.51                                          Found (%): 40.27        3.65   13.51                                          ______________________________________                                    

EXAMPLE 6

The L-lysine salt of Compound I-24 was prepared in the same manner as inExample 5 in a yield of 82%.

M.p.: 213°-214° C.

    ______________________________________                                        Elemental Analysis (for C.sub.21 H.sub.23 N.sub.4 O.sub.6 SBrClF.lH.sub.2     O)                                                                                     C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              41.22        4.12   9.16                                           Found (%): 41.55        4.04   9.19                                           ______________________________________                                    

EXAMPLE 7 Preparation of1-carboxymethyl-3-(4-bromo-2-flurobenzyl)-6-chloro-4(3H)-oxo-2(1H)-thioxothieno[2,3-d]pyrimidine(I-26)

According to the method described in Reference Example 12, 2.5 g ofN-(4-bromo-2-fluorobenzyl)-5-chloro-2-ethoxycarbonylmethylamino-3-thiophenecarboxamide,2.0 g of 1,1'-thiocarbonyldiimidazole and 20 ml of dioxane were mixedtogether and the mixture was allowed to react on a bath at a temperatureof 150° C. for 2 hours. A 80 ml quantity of ethanol was added and thesolution was cooled to room temperature. The crystals precipitated werecollected to prepare 1.4 g of1-ethoxycarbonylmethyl-3-(4-bromo-2-fluorobenzyl)-6-chloro-4(3H)-oxo-2(1H)-thioxothieno[2,3-d]pyrimidineas a crude product. This crude product was hydrolyzed in the same manneras in Example 3. That is, 15 ml of acetic acid and 15 ml of concentratedhydrochloric acid were added to this crude product, and the mixture wasrefluxed for 8 hours. Thereto 15 ml of water was added and the solutionwas cooled to room temperature. The crystals precipitated were collectedby filtration and recrystallized from 80% ethanol, giving 0.54 g of1-carboxymethyl-3-(4-bromo-2-fluorobenzyl)-6-chloro-4(3H)-oxo-2(1H)-thioxothieno[2,3-d]pyrimidinein a yield of 41%.

    ______________________________________                                        Elemental Analysis (for C.sub.15 H.sub.9 N.sub.2 O.sub.3 S.sub.2 BrClF)                C          H      N                                                  ______________________________________                                        Calcd. (%):                                                                              38.85        1.95   6.04                                           Found (%): 38.47        2.10   5.77                                           ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________     ##STR72##                              (I)                                   __________________________________________________________________________    Compound No.                                                                          R.sub.1                                                                             R.sub.2                                                                          R.sub.3      Z Yield (%)                                                                          mp (°C.)                          __________________________________________________________________________    I-1     CH.sub.3                                                                            CH.sub.3                                                                          ##STR73##   O 61   173˜176                            I-2     CH.sub.3                                                                            CH.sub.3                                                                          ##STR74##   O 53   266˜267                            I-3     (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR75##   O 61   189˜191                            I-4     (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR76##   O 44   228˜229                            I-5     H     CH.sub.3                                                                          ##STR77##   O 48   >300                                     I-6                                                                                    ##STR78##                                                                              ##STR79##   O 65   230˜234                            I-7                                                                                    ##STR80##                                                                              ##STR81##   O 65   253˜256                            I-8                                                                                    ##STR82##                                                                              ##STR83##   O 63   265˜266                            I-9                                                                                    ##STR84##                                                                             (CH.sub.2).sub.5 CH.sub.3                                                                  O 65   204˜206                            I-10    Br    CH.sub.3                                                                          ##STR85##   O 37   >300                                     I-11    Cl    CH.sub.3                                                                          ##STR86##   O 19   >300                                     I-12    CH.sub.3                                                                            H                                                                                 ##STR87##   O 66   242˜243                            I-13                                                                                   ##STR88##                                                                          H                                                                                 ##STR89##   O 71   249˜251                            I-14    CH.sub.3                                                                            CH.sub.3                                                                          ##STR90##   O 80   233˜235                            I-15                                                                                   ##STR91##                                                                              ##STR92##   O 85   228˜290                            I-16                                                                                   ##STR93##                                                                          H                                                                                 ##STR94##   O 49   160˜162                            I-17    (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR95##   O 55   203˜205                            I-18    (CH.sub.3).sub.3 C                                                                  H                                                                                 ##STR96##   O 67   194˜197                            I-19    H     H                                                                                 ##STR97##   O 77   200˜202                            I-20    H     CH.sub.3                                                                          ##STR98##   O 87   206.5˜ 208                         I-21    (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR99##   O 75   194˜196                            I-22                                                                                   ##STR100##                                                                         H                                                                                 ##STR101##  O 34   222˜226                            I-23    Br    H                                                                                 ##STR102##  O 93   244˜ 246.5                         I-24    Cl    H                                                                                 ##STR103##  O 96   221˜223                            I-25    (CH.sub.3).sub.2 CH                                                                 H                                                                                 ##STR104##  S 93   220˜221                            I-26    Cl    H                                                                                 ##STR105##  S 41   --                                       __________________________________________________________________________                        Elemental Analysis (%): Calcd. in parenthesis             Compound No.                                                                           Molecular Formula                                                                        C      H       N                                          __________________________________________________________________________    I-1      C.sub.17 H.sub.15 N.sub.2 O.sub.4 ClS                                                    (53.90)                                                                              (3.99)  (7.39)                                                         53.75  4.04    7.31                                       I-2      C.sub.17 H.sub.14 N.sub.2 O.sub.4 Cl.sub.2 S                                             (49.41)                                                                              (3.41)  (6.78)                                                         49.17  3.38    6.82                                       I-3      C.sub.18 H.sub.16 N.sub.2 O.sub.4 Cl.sub.2 S                                             (50.60)                                                                              (3.77)  (6.56)                                                         50.62  3.91    6.54                                       I-4      C.sub.18 H.sub.16 N.sub.2 O.sub.4 Cl.sub.2 S                                             (50.60)                                                                              (3.77)  (6.56)                                                         50.58  3.86    6.55                                       I-5      C.sub.16 H.sub.12 N.sub.2 O.sub.4 Cl.sub.2 S                                             (48.13)                                                                              (3.03)  (7.02)                                                         48.10  2.98    7.12                                       I-6      C.sub.20 H.sub.20 N.sub.2 O.sub.5 S                                                      (59.99)                                                                              (5.03)  (7.00)                                                         60.11  5.14    7.03                                       I-7      C.sub.20 H.sub.20 N.sub.2 O.sub.4 S                                                      (62.48)                                                                              (5.24)  (7.29)                                                         62.61  5.17    7.32                                       I-8      C.sub.19 H.sub.16 Cl.sub.2 N.sub.2 O.sub.4 S                                             (51.95)                                                                              (3.67)  (6.38)                                                         51.99  3.75    6.42                                       I-9      C.sub.18 H.sub.24 N.sub.2 O.sub.4 S                                                      (59.32)                                                                              (6.64)  (7.69)                                                         59.12  6.44    7.58                                       I-10     C.sub.16 H.sub.11 N.sub.2 O.sub.4 BrCl.sub.2 S                                           (42.71)                                                                              (2.99)  (5.53)                                                         42.52  3.12    5.36                                       I-11     C.sub.16 H.sub.11 N.sub.2 O.sub.4 Cl.sub.3 S                                             (44.31)                                                                              (2.56)  (6.46)                                                         44.22  2.38    6.34                                       I-12     C.sub.16 H.sub.12 BrFN.sub.2 O.sub.4 S                                                   (44.98)                                                                              (2.83)  (6.56)                                                         45.09  2.89    6.53                                       I-13     C.sub.21 H.sub.14 BrFN.sub.2 O.sub.4 S                                                   (51.55)                                                                              (2.88)  (5.72)                                                         51.13  3.09    5.43                                       I-14     C.sub.17 H.sub.14 BrFN.sub.2 O.sub.4 S                                                   (46.27)                                                                              (3.20)  (6.35)                                                         46.17  3.12    6.34                                       I-15     C.sub.19 H.sub.16 BrFN.sub.2 O.sub.4 S                                                   (48.83)                                                                              (3.45)  (5.99)                                                         48.70  3.41    6.03                                       I-16     C.sub.20 H.sub.18 BrFN.sub.2 O.sub.4 S                                                   (49.91)                                                                              (3.77)  (5.82)                                                         49.83  3.71    5.76                                       I-17     C.sub.18 H.sub.16 BrFN.sub.2 O.sub.4 S                                                   (47.48)                                                                              (3.54)  (6.15)                                                         47.25  3.83    6.17                                       I-18     C.sub.21 H.sub.22 Cl.sub.2 N.sub.2 O.sub.4 S                                             (51.71)                                                                              (4.11)  (6.35)                                                         51.87  4.20    6.38                                       I-19     C.sub.15 H.sub.10 BrFN.sub.2 O.sub.4 S                                                   (43.60)                                                                              (2.44)  (6.78)                                                         43.55  2.50    6.67                                       I-20     C.sub.16 H.sub.12 BrFN.sub.2 O.sub.4 S                                                   (44.98)                                                                              (2.83)  (6.56)                                                         45.02  2.78    6.38                                       I-21     C.sub.18 H.sub.16 F.sub.2 N.sub.2 O.sub.4 S                                              (54.82)                                                                              (4.09)  (7.10)                                                         55.32  4.17    7.13                                       I-22     C.sub.20 H.sub.18 Cl.sub.2 N.sub.2 O.sub.4 S                                             (52.99)                                                                              (4.00)  (6.18)                                                         52.65  3.81    5.85                                       I-23     C.sub.15 H.sub.9 Br.sub.2 FN.sub.2 O.sub.4 S                                             (36.61)                                                                              (1.84)  (5.69)                                                         36.80  1.82    5.61                                       I-24     C.sub.15 H.sub.9 BrClFN.sub.2 O.sub.4 S                                                  (40.24)                                                                              (2.03)  (6.26)                                                         40.63  1.96    6.28                                       I-25     C.sub.18 H.sub.16 BrFN.sub.2 O.sub.3 S.sub.2                                             (45.87)                                                                              (3.42)  (5.94)                                                         46.28  3.29    5.97                                       I-26     C.sub.15 H.sub.9 BrClFN.sub.2 O.sub.3 S.sub.2                                            (38.85)                                                                              (1.95)  (6.04)                                                         38.47  2.10    5.77                                       __________________________________________________________________________

PHARMACOLOGICAL TEST

Pharmacological test was carried out on the compound (I) of the presentinvention as follows.

Aldose-Reductase Inhibitory Activity

The aldose-reductase (AR) activity was evaluated by determiningspectrophotometrically the decrease in absorbance of NADPH at 340 nm dueto the reduction of the substrate, i.e., glyceraldehyde according to themethod described in Biochemical Pharmacology 25, pp 2505-2513 (1976).

The lenses of Wister male rats was homogenized with 0.5 ml of 0.1Mphosphate buffer (pH 6.2) per lens by a glass homogenizer and thehomogenate was centrifuged at 10000 rpm for 10 minutes. The supernatantobtained was used as AR.

The determination of the AR activity was conducted as follows. A 700 μlquantity of 0.1M phosphate buffer (pH 6.2), 100 μl of 2.21 mM NADPH, 100μl of AR and 5 μl of DMSO containing each of test compounds in varyingconcentrations were placed in a cell for test sample, and 800 μl of 0.1Mphosphate buffer (pH 6.2), 100 μl of 2.21 mM NADPH, 100 μl of AR and 5μl of DMSO were placed in a cell for control. Then the solutions in thecells were thoroughly mixed together and the mixtures were maintained at30° C. Then 100 μl of 100 mM glyceraldehyde maintained at 30° C. wasadded to a cell for test sample and quickly blended to initiate thereaction. The AR activity was determined from the rate of change ofabsorbance per minute in the linear part of variations of absorbanceduring a period of from 1 minute to three minutes after the start of thereaction, and a dose-response curve was drawn. An IC₅₀, i.e., aconcentration exhibiting 50% inhibition, was calculated from thedose-response curve.

    ______________________________________                                        Compound          IC.sub.50 (× 10.sup.-8 mole/l)                        ______________________________________                                        I-1                   7.5                                                     I-2                   2.0                                                     I-3                   2.6                                                     I-4                   1.7                                                     I-5                   3.0                                                     I-8                   4.2                                                     I-10                  2.6                                                     I-11                  2.5                                                     I-13                  3.4                                                     I-14                  2.1                                                     I-15                  2.3                                                     I-16                  3.0                                                     I-17                  2.2                                                     I-19                  2.0                                                     I-20                  2.4                                                     I-24    (Lysine salt) 2.5                                                     ______________________________________                                    

Preparation of pharmaceutical compositions containing the compounds ofthe present invention is described below in Preparation Examples.

PREPARATION EXAMPLE 1 (TABLETS)

A tablet was prepared from the following composition.

    ______________________________________                                        Compound I-17             100 mg                                              Lactose                   47 mg                                               Corn starch               50 mg                                               Crystalline cellulose     50 mg                                               Hydroxypropyl cellulose   15 mg                                               Talc                      2 mg                                                Magnesium stearate        2 mg                                                Ethyl cellulose           30 mg                                               Unsaturated fatty acid glyceride                                                                        2 mg                                                Titanium dioxide          2 mg                                                Total                     300 mg                                              ______________________________________                                    

PREPARATION EXAMPLE 2 (CAPSULES)

An encapsulated preparation was formulated from the followingcomposition.

    ______________________________________                                        Compound I-24           50 mg                                                 Lactose                 50 mg                                                 Corn Starch             47 mg                                                 Crystalline cellulose   50 mg                                                 Talc                    2 mg                                                  Magnesium stearate      1 mg                                                  Total                   200 mg                                                ______________________________________                                    

We claim:
 1. A thienopyrimidine derivative of the formula ##STR106##wherein R₁ and R₂ are the same or different and each represent hydrogen,halogen, lower alkyl, cycloalkyl or pheny, R₁ and R₂ taken together mayform a ring with an alkylene chain, R₃ represents lower alkyl or a groupof the formula ##STR107## (in which R₄ is lower alkyl, lower alkoxy orhalogen, m is 0, 1 or 2, and R₅ is hydrogen or halogen) and Z is oxygenor sulfur, or a pharmaceutically acceptable salt thereof.
 2. Athienopyrimidine derivative or a pharmaceutically acceptable saltthereof as defined in claim 1 wherein R₁ is hydrogen, methyl, isopropylor halogen, R₂ is hydrogen or methyl and R₃ is 3,4-dichlorobenzyl,2,4-dichlorobenzyl or 4-bromo-2-fluorobenzyl and z is oxygen or sulfur.3. A thienopyrimidine derivative or a pharmaceutically acceptable saltthereof as defined in claim 1 or 2 wherein R₁ is isopropyl, chlorine orbromine, R₂ is hydrogen and R₃ is 4-bromo-2-fluorobenzyl and z isoxygen.
 4. A pharmaceutical composition comprising an effective amountof at least one thienopyrimidine derivative of the formula ##STR108##wherein R₁ and R₂ are the same or different and each represent hydrogen,halogen, lower alkyl, cycloalkyl or pheny, R₁ and R₂ taken together mayform a ring with an alkylene chain, R₃ represents lower alkyl or a groupof the formula ##STR109## (in which R₄ is lower alkyl, lower alkoxy orhalogen, m is 0, 1 or 2, and R₅ is hydrogen or halogen) and Z is oxygenor sulfur, or pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or excipient therefor.
 5. Analdose-reductase inhibitor comprising an effective amount of at leastone thienopyrimidine derivative of the formula ##STR110## wherein R₁ orR₂ are the same or different and each represent hydrogen, halogen, loweralkyl, cycloalkyl or pheny, R₁ and R₂ taken together may form a ringwith an alkylene chain, R₃ represents lower alkyl or a group of theformula ##STR111## (in which R₄ is lower alkyl, lower alkoxy or halogen,m is 0, 1 or 2, and R₅ is hydrogen or halogen) and Z is oxygen orsulfur, or pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or excipient therefor.